Perfusion of blood to tissue is extremely important to cell and organ viability. Lack of blood flow, or ischemia, can lead to the deleterious consequences associated with stroke, myocardial infarction, kidney failure, pulmonary embolism, avascalar necrosis of the hip, etc. There are also abnormal conditions that may result in increased blood flow that would be useful to noninvasively assess, such as is found in certain tumors, uterine fibroids, avascular malformations, and the like.
There are a number of methods that have been developed over the years to determine amounts of blood flow using freely diffusible. A nonradioactive isotope of xenon has been used as a contrast agent in X-ray Computed Tomography (CT). A radioactive isotope of xenon has been radionuclide tracer studies. However, xenon is an anesthesia and must be used with caution. Radioactive isotopes of oxygen and fluorine have been used for assessment of blood flow via PET imaging techniques. Although these techniques are useful, their invasive nature has limited widespread implementation. Magnetic resonance imaging (MRI) methods offer the possibility of noninvasively determining perfusion.
MRI has traditionally used exogenous contrast agents injected intravenously in order to measure blood flow. The most commonly used agents are chelates of metals (gadolinium and manganese) that enhance longitudinal (T1) relaxivity and result in bright areas on T1 weighted images. The change in intensity can be used to calculate perfusion rates. The most commonly used MRI contrast agent is gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). This is introduced into the bloodstream by intravenous injection. As the coast agent flows into the tissue area where an image will be acquired (the imaging plane), it produces a unique signal that can be imaged through a variety of image acquisition techniques. Using contrast agents has a number of drawbacks, however, including: 1) the need for rapid imaging to capture the first pass of the contrast agent before it enters the veins, which could produce signal that can interfere with the arteries; 2) the need for accurate timing to begin the image acquisition to ensure bright arterial and dark venous signal; 3) inability to signal average to improve image quality due to the rapidly moving contrast agent; 4) possible adverse patient reaction to the contrast agent; and 5) cost of the contrast agent, especially in high-dose perfusion imaging experiments, in which the use of double- or triple-dose contrast could add hundreds of dollars to the cost of the exam.
MRI methods have been developed that are based on the use of water in the blood as an endogenous agent to produce image contrast. The advantage of this class of methods is that these techniques are entirely noninvasive and repeated measurements can be made for long periods of time. One of the first attempts to use blood water as an endogenous tracer was by Denis Le Bihan, et al. who used large magnetic field gradients to sensitize the image to small motions, including diffusion and perfusion. The problems associated with Le Bihan's method is that it is extremely sensitive to bulk motion and that it is difficult to segregate the contributions of perfusion to changes in signal intensity.
Another class of techniques involves measuring the signal difference between a image acquired after excitation ("tagging") of spins outside an imaging plane and an image acquired without exciting the spins outside the imaging plane. The signal difference between these two images is due to perfusion of tagged spins from outside the imaging plane to inside the imaging plane. This class of techniques is commonly referred to as Arterial Spin Tagging (AST) or Arterial Spin Labeling (ASL).
This class of imaging techniques creates contrast through the use of strategies that tag spins that subsequently flow into the imaging plane. The resulting image data can be used to produce either a perfusion-weighted image or can be used to calculate a perfusion map where intensities are proportional to flow in ml/100 g.sub.tissue min. The mathematics used to produce the perfusion maps is derived from steady-state equations for the kinetics of a freely diffusible tracer.
One of the original AST methods is described in U.S. Pat. No. 5,402,785 of Leigh, et al. and in the articles of Detre, et al. and Williams, et al. This imaging sequence tags spins flowing through a plane proximal to the imaging plane either with an inversion (180.degree.) or saturation (90.degree.) RF pulse. The spins flow into the imaging plane and decrease the signal. The effect of perfused spins into the imaging plane is determined by subtracting the tagged image from a control image. The tagged image not only has signal decrease from tagged blood, but from magnetization transfer (MT) saturation caused in the imaging plane by the off-resonance tagging pulse. In order to account for this, a "tagging" pulse is applied an equal distance on the distal side of the imaging plane.
There are several drawbacks to this method. (1) The RF pulses must be applied for long period in order to allow the tagged spins to reach a steady-state in the imaging plane. This can lead to SAR (specific absorption rate) problems. (2) As the spins are being tagged in the distal plane, previously excited spins are losing their tag in the imaging plane due to longitudinal T1 relaxation. (3) The tagging plane must be carefully placed in order to tag inflowing spins. This is not so hard to do in the head where tagging can be performed using a axial plane through the carotid arteries. Tagging the heart and other parts of the body would be difficult. (4) The tagging in the control image can result in the excitation of spins in the venous blood.
U.S. Pat. No. 5,846,197 of Edelman, et al., and the article of Edelman, et al., describe another method called Signal Targeting with Alternating Radiofrequency (STAR) which is similar to Leigh's method but uses a non-steady state tagging of arterial spins by inverting a thick slab proximal to the imaging plane proximal to the imaging plane. The tagged image is acquired and subtracted from a control image in which no tagging is performed. The disadvantages of this technique are similar to Leigh's method in that the tagging plane must be carefully placed. Another disadvantage of STAR is that it did not (as originally proposed) properly account for signal loss due to MT effects.
The other category of spin-tagging techniques involve tagging spins on a "slice" of tissue centered on the imaging plane. Existing methods are FAIR (Flow-sensitive Alternating Inversion Recovery) by Kim et al.; UNFAIR (Uninverted Flow-sensitive Alternating Inversion Recovery, by Helpern et al.; and FIBB (Functional Imaging with pulsed Black Blood).
FAIR (S. G, Kim) is an imaging method that acquires two images: One following a spatially selective RF pulse and one following a nonselective pulse. The difference between the two images yields a perfusion weighted image. One of the main drawbacks with FAIR is the dependence on the order of image subtraction between the control image and the tagged image. FAIR has all spins in the imaging plane inverted. The tissue spins in the imaging plane relax back towards a ground state. In the tagged image, water spins that are fully relaxed from outside the imaging plane flow into the tissue and cause the tissue to relax faster than in the control image (in which the water spins from outside the imaging plan are inverted). Different issues have different T.sub.I, which is to say they will relax at different rates. After the initial inversion pulse, spins are inverted and have a large, negative signal. As they relax, they pass through the x-y plane, at which point they produce no signal. They continue to relax until they align with the positive z-axis, and have maximal positive signal. Thus the signal goes big to small to big. Different tissues do this at different rates. One advantage that EST has over FAIR is that the order of image subtraction does not change as a function of time after inversion (Ti), i.e., in EST the tag image is always subtracted from the control image. In areas where there are tissues with different longitudinal relation times (T.sub.I), (such as the brain with gray and white matter), there are values of T.sub.I where one cannot choose a proper order of image subtraction for FAIR; One order will improperly zero the gray matter and the other order will improperly null white matter. EST does not have this problem.
Another method, UNFAIR (Helpern et al.) as originally proposed uses two selective inversion pulses, one of which is wider than the other. This leaves the stationary tissue at equilibrium values and the spins of the water inverted in the tagged image. Use of a wide selective tagging pulse introduces potential error into image data, particularly for fast-flow tissue such as kidney. Perfusion is observed by observing spins from the periphery of the imaging plane (inverted by a wide selective pulse) that have flowed into the imaging plane (whose spins are reinverted by the narrow selective pulse). Error will occur when equilibrium spins of fluid outside the wide, inverted area flow into the imaging plane. Such untagged equilibrium spins will have a signature nearly identical to the reinverted spins in the imaging plane, this will cancel out some of the signal of inverted spins flowing into the plane. Thus, UNFAIR may show less perfusion than actually exists. EST avoids this problem by inverting all spins outside the imaging plane. Another disadvantage of the UNFAIR method is that it acquires one line of k-spacer per tag, which limits the amount of data and thereby the spatial resolution that can be obtained in a reasonable amount of time. This method has only been demonstrated to using a 64.times.64 matrix. This 64.times.64 matrix required 64 separate excitations, followed by time to allow the spins to relax (referred to as the TR). TR is typically 3-4 seconds, so this low resolution image would require 3-4 minutes. A 256.times.256 image with 4 signal averages would require close to 70 minutes per slice, which is too long to be clinically useful.